Acute-transforming retroviruses carry in their genomes specific oncogenes that arose from recombination events between nontransforming viruses and normal cellular genes (proto-oncogenes or c-onc genes) that control growth and/or differentiation. In most of these retroviruses a single transforming protein is synthesized from the viral oncogene, and this protein product is responsible for initiation and maintenance of the transformed, cancerous state. About 30 acute-transforming retrovirus isolates have been reported so far, and these have been found to harbor about 20 distinct oncogenes. The fms, erbB, sis, and neu oncogenes are known to have glycosylated expression products, and the fms and erbB glycoproteins are ultimately expressed in the plasma membrane. In general, the insertion of the cellular gene within the viral genetic framework resulted in two critical alterations that permit a normal cellular gene to function in an uncontrolled manner within infected cells. First, the virus has provided a strong promoter for the cellular gene, enabling the overproduction of the acquired cellular gene, and second, in almost all cases the acquired cellular gene has been modified either through truncation or mutation. These quantitative and qualitative changes are believed to be important in neoplastic transformation by acute-transforming retroviruses and offer clues to the mechanism of transformation in the various viral oncogenes. It is therefore important to understand differences and similarities between the various v-onc and c-onc gene products.
In the specific case of the McDonough strain of feline sarcoma virus (SM-FeSV), the viral oncogene is called v-fms. This defective transforming virus was probably derived from a nondefective feline leukemia virus through in-frame insertion and replacement of part of the viral gag and all of the polymerase gene with an oncogene termed v-fms. The primary translation product of the v-fms oncogene is therefore a fusion protein of 160 kd initiating in gag and terminating at the end of v-fms (P160.sup.gag-fms). Signal sequences at the start of gag direct the protein to the endoplasmic reticulum (ER) where carbohydrate is added to asparagine residues to give gP180.sup.gag-fms, and cleavage of the gag sequences yields gp120.sup.fms plus p55.sup.gag. A hydrophobic stretch of amino acids about midway through the sequence insures a transmembrane orientation with the C-terminal end of the fms proteins in the cytoplasm. Further processing in the Golgi results in a gp140.sup.fms species that ultimately is expressed on the plasma membrane. The gp140.sup.fms is associated with coated pits on the cell surface, is processed through endocytosis, and may function as a modified growth factor receptor on the surface of SM-FeSV-transformed cells.
The physical properties, cellular location, and fact that gp140.sup.v-fms undergoes endocytosis through coated pits and vesicles all point to a functional analogy with growth factor receptors. The gp140.sup.v-fms also exhibits an associated tyrosine kinase activity as do many growth factor receptors. Furthermore, the amino acid sequences of v-fms and acknowledge tyrosine kinases such as pp60.sup.v-src are homologous.
It would be advantageous to discover ways to intervene in the cellular expression of acute-transforming retroviruses and thereby cause transformed cells to revert to the normal phenotype (cancer remission). It would also be advantageous to discover the normal cellular counterparts of transforming oncogenes, so that the growth and/or differentiation of cells that express c-onc genes, either normally or abnormally, could be likewise modulated for therapeutic effect.